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PNAS-4, a novel pro-apoptotic gene, can potentiate antineoplastic effects of cisplatin

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Abstract

Purpose

PNAS-4, a novel pro-apoptotic gene activated during the early response to DNA damage, can inhibit proliferation via apoptosis when overexpressed in some tumor cells. The objectives of this study were to determine whether PNAS-4 could enhance apoptosis induced by cisplatin besides its induction of apoptosis, and to evaluate the usefulness of combined treatment with mouse PNAS-4 (mPNAS-4) gene therapy and low-dose cisplatin chemotherapy in the inhibition of tumor growth in colon carcinoma (CT26) and Lewis lung carcinoma (LL/2) murine models.

Methods

In this study, the in vitro growth-inhibitory and pro-apoptotic effects of PNAS-4 and/or cisplatin on CT26, LL/2, and SKOV3 cancer cells were assessed by MTT assay, flow cytometric analysis, DNA fragmentation, and morphological analysis, respectively. The in vivo antitumor activity of combined treatment with mPNAS-4 gene therapy and low-dose cisplatin were evaluated in the inhibition of tumor growth in colon carcinoma (CT26) and Lewis lung carcinoma (LL/2) murine models. Tumor volume and survival time were observed. Induction of apoptosis was also assessed in tumor tissues.

Results

In vitro, PNAS-4 inhibited proliferation of colon carcinoma (CT26), Lewis lung carcinoma (LL/2) and human ovarian cancer (SKOV3) cell lines via apoptosis, and significantly enhanced the apoptosis of CT26, LL/2, and SKOV3 cells induced by cisplatin. In vivo systemic administration of expression plasmid encoding mPNAS-4 (pcDNA3.1-mPS) and cisplatin, significantly decreased tumor growth through increased tumor cell apoptosis compared to treatment with mPNAS-4 or cisplatin alone.

Conclusions

Our data suggests that the combined treatment with mPNAS-4 plus cisplatin may augment the induction of apoptosis in tumor cells in vitro and in vivo, and that the augmented antitumor activity in vivo may result from the increased induction of apoptosis. The present study may provide a novel way to augment the antitumor efficacy of cytotoxic chemotherapy.

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Abbreviations

HLE B-3:

Human lens epithelial cells

pcDNA3.1-mPS:

pcDNA3.1 Expression plasmid encoding mouse PNAS-4 gene

pcDNA3.1-hPS:

pcDNA3.1 Expression plasmid encoding human PNAS-4 gene

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling

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Acknowledgments

The authors thank Dr. Ning Xu for her advice, discussion, and critical review of the manuscript, and Dr. Yang Wan for their technical support. This work was supported by National Key Basic Research Program of China (2004CB518800, 2005CB522506).

Conflicts of interest statement

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, 1# Keyuan Road 4, Gaopeng Street, High Technological Development Zone, 610041, Chengdu, China

    Zhu Yuan, Fei Yan, Yong-sheng Wang, Lan-tu Gou, Xin-yu Zhao, Song-tao Lai, Hong-xin Deng, Jiong Li, Zhen-yu Ding, Shao-qun Xiong, Bing Kan, Yong-qiu Mao, Li-juan Chen & Yu-quan Wei

  2. Department of Gynecology and Obstetrics, West China Second Hospital, West China Medical School, Sichuan University, 610041, Chengdu, China

    Xia Zhao

  3. Cancer Center, Chengdu Military General Hospital, 610083, Chengdu, China

    Huan-yi Liu

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  1. Zhu Yuan
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  2. Fei Yan
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  3. Yong-sheng Wang
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Corresponding authors

Correspondence to Hong-xin Deng or Xia Zhao.

Additional information

Z. Yuan and F. Yan contributed equally to this work.

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Yuan, Z., Yan, F., Wang, Ys. et al. PNAS-4, a novel pro-apoptotic gene, can potentiate antineoplastic effects of cisplatin. Cancer Chemother Pharmacol 65, 13–25 (2009). https://doi.org/10.1007/s00280-009-0998-5

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  • DOI: https://doi.org/10.1007/s00280-009-0998-5

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